Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice

Mario de la Fuente Revenga, Bohan Zhu, Christopher A. Guevara, Lynette B. Naler, Justin M. Saunders, Zirui Zhou, Rudy Toneatti, Salvador Sierra, Jennifer T. Wolstenholme, Patrick M. Beardsley, George W. Huntley, Chang Lu, Javier González-Maeso

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


Clinical evidence suggests that rapid and sustained antidepressant action can be attained with a single exposure to psychedelics. However, the biological substrates and key mediators of psychedelics’ enduring action remain unknown. Here, we show that a single administration of the psychedelic DOI produces fast-acting effects on frontal cortex dendritic spine structure and acceleration of fear extinction via the 5-HT2A receptor. Additionally, a single dose of DOI leads to changes in chromatin organization, particularly at enhancer regions of genes involved in synaptic assembly that stretch for days after the psychedelic exposure. These DOI-induced alterations in the neuronal epigenome overlap with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder. Together, these data support that epigenomic-driven changes in synaptic plasticity sustain psychedelics’ long-lasting antidepressant action but also warn about potential substrate overlap with genetic risks for certain psychiatric conditions.

Original languageEnglish
Article number109836
JournalCell Reports
Issue number3
StatePublished - 19 Oct 2021


  • 5-HT2A receptor
  • GPCR
  • depression
  • epigenomics
  • hallucinogens
  • psychedelics
  • psychosis
  • schizophrenia
  • serotonin (5-HT)
  • synaptic plasticity


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